Chronic pain, a major clinical problem causing significant morbidity and economic impact, is presently treated with limited success, in large part due to inadequate understanding of its underlying mechanisms. The objective of this Program Project grant is to elucidate cellular mechanisms of acute and chronic nociception in the primary afferent nociceptor. Because some of the mechanisms we will investigate appear to be selective for the nociceptor, these studies can potentially identify novel highly selective nociceptor-targeted analgesic therapies. This group of PIs will contribute very complementary arrays of knowledge and skills, conduct formal and informal research collaborations, and share equipment and techniques, especially those related to anatomy and transgenic models of acute and chronic pain. Drs. Jon Levine (Project #1) and Robert Messing (Project #2) will evaluate the contribution of PKCepsilon to nociceptor function. Specifically, Dr. Levine will focus on second messengers in nociceptors upstream of PKCepsilon, and Dr. Messing will determine targets that lie downstream of PKCepsilon. Together, these two projects will provide the first detailed description of this nociceptor-specific second messenger signaling pathway and its function in acute and chronic pain. Dr. Mark von Zastrow (Project #3) will explore the distribution and regulation of opioid (antinociceptive) and beta2- adrenergic (pronociceptive, upstream of PKCepsilon) receptors in nociceptors. He will also analyze the role of G- protein related kinase 2 (GRK2) in setting the sensitivity of the function of these two receptors in nociceptors. Finally, an Anatomy Core headed by Dr. Allan Basbaum, (Core B) will provide high very level support for the large number of anatomical studies in all three projects. This multidisciplinary approach to elucidating the function of nociceptors will significantly increase our understanding of mechanisms underlying pain syndromes and will elucidate key targets for novel therapies for acute and chronic pain.